Coupling reactions useful in the preparation of (1h-tetrazol-5-yl) biphenyl derivatives

ABSTRACT

The present invention relates to a process for the manufacture of intermediates that may be used for the manufacture of ARBs (also called angiotension II receptor antagonists or AT 1  receptor antagonists) comprising as a common structural feature a tetrazole ring.

This application is a Divisional of application Ser. No. 10/588,169,filed Aug. 2, 2006, which is a National Phase Application ofPCT/EP05/00978, filed Feb. 1, 2005, which claims benefit of UnitedKingdom application No. 0402262.0, filed Feb. 2, 2004 The contents ofthe applications are incorporated herein in their entirety.

The present invention relates to a process for the manufacture ofintermediates that may be used for the manufacture of ARBs (also calledangiotension II receptor antagonists or AT₁ receptor antagonists)comprising a tetrazole ring as a common structural feature. ARBs can,for example, be used for the treatment of hypertension and relateddiseases and conditions.

For example, mention may be made of ARBs that are selected from thegroup consisting of valsartan (cf. EP 443983), losartan (cf. EP 253310),candesartan (cf. EP 459136), eprosartan (cf. EP 403159), irbesartan (cf.EP 454511), olmesartan (cf. EP 503785), and tasosartan (cf. EP 539086),or, in each case, a pharmaceutically acceptable salt thereof.

More specifically, all these ARBs comprise the following commonstructural element of formula (A):

The manufacture of an aldehyde of formula (I A), corresponding to saidelement of formula (A), is a critical step in the manufacture of theabove-mentioned angiotensin II receptor antagonists. Various aryl-arylcoupling reactions to form the biphenyl moiety in an aldehyde of formula(I A) have been recommended in the art.

EP 550313 describes the preparation of protected2′-(1H-tetrazol-5-yl)-biphenyl-4-carbaldehyde involving transition metalcatalyzed coupling of protected 5-(2-iodophenyl)-2H-tetrazole with anorganozinc reagent or an arylboronic acid. The formation ofstoichiometric quantities of zinc salt waste in the first case, and theseveral chemical steps required for the preparation of the arylboronicacid in the second case, and the formation of stoichiometric quantitiesof iodide waste in both cases are regarded as disadvantages.

U.S. Pat. No. 5,468,867 discloses the preparation of protected2′-(1H-tetrazol-5-yl)-biphenyl-4-carbaldehyde involving metallation ofan arylhalide with an organometallic base such as an alkyllithiumreagent followed by coupling, e.g., with protected5-(2-methoxyphenyl)-2H-tetrazole. A disadvantage of this procedure isthe formation of stoichiometric quantities of reactive, halogencontaining waste.

The objective of the present invention is to provide a novel synthesisfor compounds of formulae (I) and (IC)

wherein Y is a tetrazole protecting group, R₁ and R₂, independently ofone another, represent C₁-C₁₀-alkyl, or R₁ and R₂ combined together formC₂-C₁₀-alkylene, and R₃ represents a hydroxyl protecting group; that (1)does not have the disadvantages described above, (2) allows for the useof such tetrazole protecting groups which are easily removed in thepresence of a Bronsted acid, (3) does not require large excesses ofreagents, (4) gives high yields, (5) gives a minimum of waste,especially no stoichiometric amounts of reactive or environmentallyproblematic waste, and (6) is economically attractive.

Compounds of formulae (I) and (IC) may be easily converted to compoundsof formula (I A) and, therefore, are important intermediates for themanufacture of ARBs having the structural feature corresponding toformula (A), as described, e.g., in International PCT Application No. WO04/026847.

It has surprisingly been found that the process according to the presentinvention meets at least the above objectives.

In one aspect, the present invention relates to a process for themanufacture of a compound of formula (I)

wherein Y represents a tetrazole protecting group, and R₁ and R₂,independently of one another, represent C₁-C₁₀-alkyl, or R₁ and R₂combined together form C₂-C₁₀-alkylene; comprising(a) reacting a compound of formula (II a)

wherein Hal is chlorine, bromine or iodine, with an active form ofmagnesium in an appropriate solvent;(b) reacting a resulting aryl magnesium halide compound of formula (IIb)

in the presence of a transition metal catalyst and a catalyticallyeffective amount of a metal salt additive, with a compound of formula(II c)

wherein X is a substituent which, when bound to a phenyl ring, is notconsiderably replaceable at room temperature by an arylmagnesium halidereagent of formula (II b) in the absence of a catalyst; and, ifnecessary, isolating a resulting compound of formula (I).

In another aspect, the present invention relates to a process for themanufacture of a compound of formula (I C)

wherein Y represents a tetrazole protecting group, and R₃ represents ahydroxyl protecting group; comprising(a′) reacting a compound of formula (III a)

wherein Hal is chlorine, bromine or iodine, with an active form ofmagnesium in an appropriate solvent;(b′) reacting a resulting aryl magnesium halide compound of formula (IIIb)

in the presence of a transition metal catalyst and a catalyticallyeffective amount of a metal salt additive, with a compound of formula(II c)

wherein X is a substituent which, when bound to a phenyl ring, is notconsiderably replaceable at room temperature by an aryl magnesium halidereagent of formula (III b) in the absence of a catalyst; and, ifnecessary, isolating a resulting compound of formula (I C).

A further aspect of the present invention is combining steps (a) and/or(b), or steps (a′) and/or (b′), with a subsequent deprotection step (c)resulting in the formation of a compound of formula (I A) or (I B)

respectively.

The resulting compound of formula (I A) or (I B), respectively, issubsequently isolated and may be employed as an intermediate in thepreparation of ARBs as referred herein above. It is obvious to thoseskilled in the art that a compound of formula (I B) may be readilyconverted to a compound of formula (I A) by treatment with an oxidizingagent according to methods well known in the art.

The reactions described above and below in the variants are carried out,for example, in the absence or, customarily, in the presence of asuitable solvent or diluent or a mixture thereof, the reaction, asrequired, being carried out with cooling, at room temperature or withwarming, for example in a temperature range from about −80° C. up to theboiling point of the reaction medium, preferably from about −10° C. toabout 140° C., and, if necessary, in a closed vessel, under pressure, inan inert gas atmosphere and/or under anhydrous conditions.

The purpose of introducing protecting groups, e.g., Y and R₃, is toprotect the functional groups, e.g., tetrazole and a hydroxyl group,respectively, from undesired reactions with reaction components underthe conditions used for carrying out the process of the presentinvention. The choice of protecting groups is known to those skilled inthe art and depends on the nature of the functional group to beprotected and the reaction conditions.

Well-known protecting groups that meet these conditions and theirintroduction and removal are described, e.g., in McOmie, “ProtectiveGroups in Organic Chemistry”, Plenum Press, London, N.Y. (1973); andGreene and Wuts, “Protective Groups in Organic Synthesis”, John Wileyand Sons, Inc., NY (1999).

A tetrazole protecting group (Y) is, for example, selected from thegroup consisting of tert-C₄-C₇-alkyl such as tert-butyl; methyl that issubstituted by one, two or three substituents selected from C₁-C₇-alkyland C₁-C₇-alkoxy, for example 1-ethoxyethyl, 1-methoxy-1-methylethyl;2-tetrahydropyranyl; 2-tetrahydrofuranyl; C₁-C₂-alkyl that is mono-, dior trisubstituted by phenyl, such as benzyl or benzhydryl or trityl,wherein the phenyl ring is unsubstituted or substituted by one or more,e.g. two or three, substituents e.g. those selected from the groupconsisting of tert-C₁-C₇-alkyl, C₁-C₇-alkoxy, C₂-C₈-alkanoyloxy;piperonyl; 1-methyl-1-phenylethyl; fluorenyl; methylthiomethyl; silylsuch as tri-C₁-C₄-alkylsilyl, for example, trimethylsilyl, triethylsilylor tert-butyl-dimethylsilyl, or di-C₁-C₄-alkyl-phenylsilyl, for example,dimethyl-phenylsilyl; C₁-C₇-alkyl-sulphonyl; arylsulphonyl such asphenylsulphonyl wherein the phenyl ring is un-substituted or substitutedby one or more, e.g. two or three, substituents e.g. those selected fromthe group consisting of C₁-C₇-alkyl, C₁-C₇-alkoxy, C₂-C₈-alkanoyl-oxy;C₂-C₈-alkanoyl such as acetyl or valeroyl; and esterified carboxy suchas C₁-C₇-alkoxy-carbonyl, for example, methoxy-, ethoxy- ortert-butyloxy-carbonyl. Likewise, a tetrazole protecting group (Y) alsomay be a cation, e.g. of an alkali metal or an earth alkali metal, forexample Li(I), Na(I), K(I), Rb(I), Cs(I), Mg(II), Ca(II) and Sr(II).

Examples of preferred protecting groups Y are tert-butyl, benzyl,p-methoxybenzyl, 3,4-dimethoxybenzyl, 1-methyl-1-phenylethyl,triphenylmethyl, (p-methoxyphenyl)diphenylmethyl, benzyloxymethyl,methoxymethyl, ethoxymethyl, 1-butoxyethyl, 1-ethoxyethyl,2-tetrahydropyranyl, 2-tetrahydrofuranyl, 1-methoxy-1-methylethyl,1-methoxycyclohexyl, 1-ethoxycyclohexyl, trimethylsilyl andtriethylsilyl.

Particularly preferred protecting groups Y are 1-butoxyethyl,1-ethoxyethyl, 2-tetrahydropyranyl and 2-tetrahydrofuranyl.

A hydroxyl protecting group (R₃) is, for example, selected from thegroup consisting of tert-C₄-C₇-alkyl such as tert-butyl; methyl that issubstituted by one, two or three substituents selected from C₁-C₇-alkyland C₁-C₇-alkoxy, for example 1-ethoxyethyl, 1-methoxy-1-methylethyl;2-tetrahydropyranyl; 2-tetrahydrofuranyl; C₁-C₂-alkyl that is mono-, dior trisubstituted by phenyl, such as benzyl or benzhydryl or trityl,wherein the phenyl ring is unsubstituted or substituted by one or more,e.g. two or three, substituents e.g. those selected from the groupconsisting of tert-C₁-C₇-alkyl, C₁-C₇-alkoxy, C₂-C₈-alkanoyloxy;piperonyl; 1-methyl-1-phenylethyl; fluorenyl; methylthiomethyl; silylsuch as tri-C₁-C₄-alkylsilyl, for example, trimethylsilyl, triethylsilylor tert-butyl-dimethylsilyl, or di-C₁-C₄-alkyl-phenylsilyl, for example,dimethyl-phenylsilyl; 2,2-dimethylpropanoyl (i.e. pivaloyl) andesterified carboxy such as tert-butyloxy-carbonyl andbenzyloxy-carbonyl.

Examples of preferred protecting groups R₃ are 2-tetrahydropyranyl,2-tetrahydrofuranyl, 1-butoxyethyl and 1-ethoxyethyl.

The general terms used hereinbefore and hereinafter have the followingmeanings, unless defined otherwise:

C₁-C₁₀-Alkyl is, for example, C₁-C₇-alkyl, such as methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl or acorresponding pentyl, hexyl or heptyl residue. C₁-C₄-alkyl, especiallymethyl or ethyl, is preferred.

C₂-C₁₀-Alkylene is, for example, C₂-C₆-alkylene, such as ethylene,propylene, butylene, 1,2-dimethylethylene, 2,2-dimethylpropylene or1,4-dimethyl-1,4-butylene. C₂-C₄-Alkylene, especially, ethylene orpropylene, is preferred.

Hal represents in particular chlorine and bromine.

C₁-C₇-Alkoxy is, for example, methoxy, ethoxy, n-propyloxy,isopropyloxy, n-butyloxy, iso-butyloxy, sec-butyloxy, tert-butyloxy or acorresponding pentyloxy, hexyloxy, or heptyloxy residue. C₁-C₄-alkoxy ispreferred. Especially preferred is methoxy, ethoxy and butoxy.

C₂-C₈-Alkanoyl is, for example, C₂-C₅-alkanoyl such as acetyl,propionyl, butyryl, valeroyl, or pivaloyl. Especially preferred isacetyl.

Steps (a) and (a′):

An active form of magnesium is, for example, magnesium turnings of thetype normally used for such transformations, magnesium chips, magnesiumpowder or magnesium rods.

Furthermore, an active form of magnesium is magnesium that is activatedby a catalytic amount of iodine, bromine, 1,2-dibromoethane, a hydridereagent or the arylmagnesium halide reagent intended to be prepared.

A suitable amount of magnesium is 1.0 to 1.8 molar equivalents,preferably 1.0 to 1.2 molar equivalents, with respect to the amount of acompound of formula (II a) or (III a) used.

The reaction is carried out, for example, in a suitable inert solvent ora mixture of solvents. Inert solvents conventionally do not react withthe corresponding starting material of formula (II a) or (III a).Appropriate solvents are ethereal solvents, such as ethyl ether,tert-butyl methyl ether, tetrahydrofuran, butyl ether,1,2-dimethoxyethane or 1,2-diethoxyethane, or a mixture of two or moreof these solvents, or a mixture of one of these solvents and an aromaticsolvent such as toluene or xylene. A preferred solvent istetrahydrofuran.

A suitable reaction temperature preferably is between 0° and 75° C.,more preferably between 10° and 35° C.

Steps (b) and (b′):

The coupling step (b) or (b′) is carried out in the presence of atransition metal catalyst. A suitable transition metal is, for example,nickel, palladium, platinum, cobalt, manganese or copper. A usefultransition metal salt is, for example, a nickel(II), a palladium(II), aplatinum(II), a cobalt(II), a manganese(II), a copper(I) or a copper(II)salt such as the chloride, bromide, iodide, hydroxide, oxide, acetate,hydroxyacetate, propionate, succinate, trifluoroacetate,acetylacetonate, nitrate, cyanide, sulfate, trifluoromethanesulfonate,methanesulfonate, benzenesulfonate or p-toluenesulfonate thereof.

A suitable transition metal catalyst is preferably a complex of atransition metal or a transition metal salt and one, two or up to fourcoordinating ligands. The transition metal catalyst may be preformed orit may be generated in situ in the reaction mixture. A suitabletransition metal catalyst may also be the uncomplexed transition metalin its elemental form or an uncomplexed transition metal salt. Theuncomplexed transition metal or its salt may be supported on carbon,silica, alumina or diatomaceous earth.

Suitable ligands are olefins, such as 1,5-cyclooctadiene;tri(C₁-C₄-alkyl)amines, such as triethylamine andethyl-diisopropylamine; N—C₁-C₄-alkyl-piperidines, such asN-methylpiperidine; N,N,N′,N′-tetramethylethylenediamine; heterocyclicamines and diamines, such as pyridine, N-methylimidazole,2,2′-dipyridyl, 1,10-phenanthroline, wherein the ring is un-substitutedor substituted by one or more, e.g. two or three, C₁-C₄-alkyl-residues,as for example in collidine; linear and cyclic ethers containing two ormore, e.g. three or four, oxygen atoms, such as 1,2-dimethoxyethane,1,2-diethoxyethane, di(ethylene glycol) dimethyl ether and1,2-dimethoxybenzene.

Particularly suitable ligands are those containing one or two trivalentphosphorus atoms, for example, triphenylphosphine,tri(ortho-tolyl)phosphine and tri(para-tolyl)phosphine,tri(C₁-C₈-alkyl)phosphines such as trimethylphosphine,triethylphosphine, tributylphosphine, tri(1,1-dimethylethyl)phosphine,tri(C₄-C₇-cycloalkyl)phosphines such as tricyclopentylphosphine andtricyclohexylphosphine, tri(C₁-C₆-alkyl)phosphites such astrimethylphosphite, triethylphosphite and tri(1-methylethyl)phosphite,tri(C₄-C₇-cycloalkyl)phosphites such as tricyclopentylphosphite andtricyclohexylphosphite, 1,2-bis(diphenylphosphino)ethane (i.e. dppe),1,3-bis(diphenylphosphino)propane (i.e. dppp),1,4-bis(diphenylphosphino)butane (i.e. dppb),1,1′-bis(diphenylphosphino)ferrocene (i.e. dppf),1,1′-bis(di-[2-propyl]-phosphino)ferrocene,1,1′-bis(di-tert-butyl-phosphino)ferrocene,1,2-bis(diphenylphosphino)-benzene,2,2′-bis(diphenylphosphino)-1,1′-biphenyl (i.e. BIPHEP),2,2′-bis(diphenylphosphino)-1,1′-binaphtyl (i.e. BINAP),bis(2-diphenylphosphinophenyl)ether (i.e. DPEphos),9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (i.e. XANTPHOS).

Transition metal salts are derived from above specific transitionmetals.

Preferred transition metal salts are nickel(II) chloride, nickel(II)bromide and nickel(II) acetylacetonate. A particularly preferredtransition metal salt is nickel(II) chloride.

Preferred ligands are triphenylphosphine,1,2-bis(diphenylphosphino)ethane (i.e. dppe),1,3-bis(diphenylphosphino)propane (i.e. dppp),1,1′-bis(diphenylphosphino)ferrocene (i.e. dppf). A particularlypreferred ligand is 1,2-bis(diphenylphosphino)ethane (i.e. dppe).

Preferred catalysts are dichlorobis(triphenylphosphine)nickel(II),dichloro[1,2-bis(diphenylphosphino)ethane]nickel(II),dichloro[1,3-bis(diphenylphosphino)propane]-nickel(II). A particularlypreferred catalyst isdichloro[1,2bis(diphenylphosphino)ethane]-nickel(II).

The amount of nickel catalyst used is preferably between 0.05 and 2molar % relative to N-protected tetrazole starting material of formula(II c), preferably between 0.2 and 1.5 molar %.

Likewise preferred transition metal salts are palladium(II) chloride,palladium(II) bromide and palladium(II) acetate. A particularlypreferred transition metal salt is palladium(II) chloride.

Preferred ligands are triphenylphosphine,1,3-bis(diphenylphosphino)propane (i.e. dppp),1,1′-bis(diphenylphosphino)ferrocene (i.e. dppf). A particularlypreferred ligand is 1,1′-bis(diphenylphosphino)ferrocene (i.e. dppf).

Preferred palladium catalysts aredichlorobis(triphenylphosphine)palladium(II),dichloro[1,3-bis(diphenylphosphino)propane]palladium(II) anddichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) or itsdichloromethane adduct. A particularly preferred palladium catalyst isdichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II), or adichloromethane adduct thereof.

The amount of palladium catalyst used is preferably between 0.01 and 1molar % relative to N-protected tetrazole starting material (II c),preferably between 0.05 and 0.3 molar %.

The coupling reaction in step (b) or (b′) may involve a metal saltadditive. The role of the metal salt additive, which is used incatalytic amounts, is to facilitate the coupling reaction. Compared tocouplings with aryl-zinc reagents, the use of catalytic amounts of sucha metal salt additive results in the formation of less waste. Inaddition, in the presence of metal salt additive, a higher conversionsof starting material (II c) can be achieved. A useful metal saltadditive is a copper(I), copper(II), zinc(II), silver(I), cadmium(II),mercury(II), aluminum(III), gallium(III), indium(III), tin(IV),titanium(IV) and zirconium(IV) salt. Examples of such salts are thecorresponding chloride, bromide, iodide, carbonate, hydroxide, oxide,C₁-C₇-alkanoates such as the acetate and propionate, C₁-C₇-alkoxidessuch as the methoxide and ethoxide, trifluoroacetate, acetylacetonate,nitrate, cyanide, sulfate, trifluoromethanesulfonate, methanesulfonate,benzenesulfonate or para-toluenesulfonate.

Preferred metal salt additives are zinc(II) salts such as zinc(II)chloride and zinc(II) bromide. A particularly preferred metal saltadditive is zinc(II) chloride.

The amount of metal salt additive used is preferably between 0.1 and 8molar % relative to N-protected tetrazole starting material of formula(II c), preferably between 0.5 and 6 molar %.

Substituent X is a substituent that is not considerably replaceable atroom temperature by an arylmagnesium halide reagent of formula (II b) or(III b) in the absence of a transition metal catalyst. In particular, Xis, for example, chlorine or bromine. A preferred substituent X ischlorine.

When X is chlorine, the preferred transition metal of the catalyst isnickel.

When X is bromine, the preferred transition metal of the catalyst ispalladium.

Independent of the choice of catalyst, the reaction is carried out, forexample, in a suitable inert solvent or a mixture of solvents. Inertsolvents conventionally do not react with the corresponding startingmaterials of formulae (II b), (III b) and (II c).

An appropriate solvent for the reaction is an ethereal solvent, such asethyl ether, tert-butyl methyl ether, tetrahydrofuran, butyl ether,1,2-dimethoxyethane or 1,2-diethoxyethane; a dipolar aprotic solvent,such as 1-methyl-2-pyrrolidinone (i.e. NMP) and1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (i.e. DMPU); anaromatic solvent such as toluene or xylene; or a mixture of two or moresolvents selected from the above groups. A preferred solvent istetrahydrofuran.

The reaction is preferably carried out at a temperature between −10° and60° C., preferably between 10° and 35° C.

As described herein above, the present inventions provides a process forthe preparation of a protected2′-(1H-tetrazol-5-yl)-biphenyl-4-carbaldehyde of formula (I) asexemplified by the following reaction scheme

comprising coupling of a N-protected phenyltetrazole (X=Cl or Br; Y=atetrazole protecting group) with an arylmagnesium halide (Hal=Cl, Br, I;R₁, R₂=C₁-C₁₀-alkyl or combined C₂-C₁₀-alkylene) in the presence of atransition metal catalyst, which is complexed, uncomplexed or supportednickel, palladium, platinum, cobalt, manganese or copper metal or acorresponding salt thereof, and optionally a catalytic amount of a metalsalt additive, such as a copper(I), copper(II), zinc(II), silver(I),cadmium(II), mercury(II), aluminum(III), gallium(III), indium(III),tin(IV), titanium(IV) or zirconium(IV) salt, in the presence of an inertsolvent or a mixture of inert solvents.

Similarly, the present invention provides a process for the manufactureof a protected alcohol of formula (I C) as exemplified by the reactionscheme bellow

comprising coupling of a N-protected phenyltetrazole (X=Cl or Br; Y=atetrazole protecting group) with an arylmagnesium halide (Hal=Cl, Br, I;R₃=a hydroxyl protecting group) in the presence of a transition metalcatalyst, which is complexed, uncomplexed or supported nickel,palladium, platinum, cobalt, manganese or copper metal or acorresponding salt thereof, and optionally a catalytic amount of a metalsalt additive, such as a copper(I), copper(II), zinc(II), silver(I),cadmium(II), mercury(II), aluminum(III), gallium(III), indium(III),tin(IV), titanium(IV) or zirconium(IV) salt, in the presence of an inertsolvent or a mixture of inert solvents.

Preferred Hal is, for example, Br.

Preferred R₁ and R₂ are, for example, methyl.

Preferred R₃ is, for example, 2-tetrahydropyranyl.

Preferred X is, for example, Cl.

When X is chlorine, a preferred transition metal catalyst is a nickel(0)or nickel(II) complex, for example, a complex of a nickel(II) salt whichis coordinated by at least one organo phosphorus compound containingtrivalent phosphorus. Nickel(II) complexes comprising twoorganophosphorus ligands are preferred. Nickel(II) complexes withorganophosphorus ligands which contain two trivalent phosphorus atoms,such as dichloro[1,2-bis(diphenylphosphino)ethane]nickel(II) (i.e.NiCl₂(dppe)), are particularly preferred. A preferred metal saltadditive is, for example, a zinc(II) salt such as ZnCl₂ and ZnBr₂.

Preferred solvents are ethereal solvents, particularly tetrahydrofuran.

When X is chlorine, compounds of formula (I) may be prepared without themetal salt additive (e.g. ZnCl₂) in above process, i.e. catalyzing thecoupling reaction solely by the nickel catalyst.

When X is bromine, a preferred transition metal catalyst is a palladiumcomplex, for example, a complex of palladium(0) or a complex of apalladium(II) salt with at least one organophosphorus compoundcontaining trivalent phosphorus. Palladium(II) complexes comprising twoorganophosphorus ligands are preferred. Palladium(II) complexes withorganophosphorus ligands which contain two trivalent phosphorus atoms,such as dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)(i.e. PdCl₂(dppf)) or its dichloromethane adduct, are particularlypreferred.

A preferred metal salt additive is, for example, a zinc(II) salt such asZnCl₂ and ZnBr₂.

In a variation of the present invention, another embodiment of thepresent invention is a process for the manufacture of a compound offormula (I)

wherein Y represents a tetrazole protecting group, and R₁ and R₂,independently of one another, represent C₁-C₁₀-alkyl, or R₁ and R₂combined together form C₂-C₁₀-alkylene; comprising(a) reacting a compound of formula (II a)

wherein Hal is chlorine, bromine or iodine, with an active form ofmagnesium in an appropriate solvent(b) reacting a resulting aryl magnesium halide compound of formula (IIb)

in the presence of a transition metal catalyst with a compound offormula (II c)

wherein X is chlorine, in the absence of a metal salt additive; and, ifnecessary, isolating a resulting compound of formula (I).

Yet another variation of the present invention is a process for themanufacture of a compound of formula (I C)

wherein Y represents a tetrazole protecting group, and R₃ represents ahydroxyl protecting group; comprising(a′) reacting a compound of formula (III a)

wherein Hal is chlorine, bromine or iodine, with an active form ofmagnesium in an appropriate solvent;(b′) reacting a resulting aryl magnesium halide compound of formula (IIIb)

in the presence of a transition metal catalyst with a compound offormula (II c)

wherein X is chlorine, in the absence of a metal salt additive; and, ifnecessary, isolating a resulting compound of formula (I C).

A further embodiment of the present invention is the reaction step (b)or (b′), respectively, i.e., the specific reaction of a compound offormula (II b) or (III b), respectively, with a compound of formula (IIc), wherein X is chlorine. In the instant reaction, surprisingly, noaddition of a catalytically effective amount of a metal salt additive isnecessary to result in a compound of formula (I) or (I C), respectively.

In the case in which both the transition metal salt and the metal saltadditive are omitted, no significant amount of compound of formula (I)or (I C), respectively, is formed from a starting material of formula(II c), wherein X is chlorine.

Isolation Step:

The isolation of a compound of formula (I) or (I C) is carried outaccording to conventional isolation methods, such as by crystallizingthe resulting compound of formula (I) or (I C) from the reactionmixture, if desired or necessary after work-up, especially byextraction, or by chromatography of the reaction mixture, or anycombined methods.

Step (c):

For this purpose, the protecting groups of a resulting compound offormula (I) or (I C) of step (b) or (b′), respectively, are removedsequentially or in a single step under conditions of hydrolysis,preferably in the presence of a Bronsted acid.

Step (c) is carried out, for example, by dissolving a compound offormula (I) or (I C) in water or a mixture of water and an appropriateorganic solvent and subsequently treating with an acid, preferably, atan elevated temperature.

Appropriate organic solvents are ethers, such as tetrahydrofuran,1,4-dioxan, butyl ether, nitriles, such as acetonitrile, alcohols, suchas methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, isopropylacetate, toluene, xylene, acetic acid or formic acid. Preferred solventsare methanol and ethanol.

Suitable acids are Bronsted acids, such as sulfuric acid, hydrochloricacid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid,para-toluenesulfonic acid, benzoic acid, acetic acid, formic acid aswell as polymer supported Bronsted acids (e.g. acidic ion exchangeresins). Preferred acids are sulfuric acid and hydrochloric acid.

The amount of acid used is preferably between 0.05 and 2.0 equivalentswith respect to a compound of formula (I) or (I C), more preferablybetween 0.1 and 1.2 equivalents.

The reaction is carried out at a temperature between 0° C. and theboiling point of the solvent, preferably between 25° and 70° C.

The isolation of a resulting compound of formula (I A) or (I B) iscarried out according to conventional isolation methods, such as bycrystallizing a compound of formula (I A) or (I B) from the reactionmixture and, if desired or necessary after work-up, especially byextraction, or by chromatography of the reaction mixture or any combinedmethods thereof. For example, crystallization of the product isaccomplished by distilling off all or a part of the organic solvent,adding water, cooling the mixture or a combination of these measures.

Several starting materials of formulae (II a) and (III a) are known inthe art and can be prepared according to methods well known in the art.For example, a compound of formula (II a) may be obtained byconventional acid catalyzed acetalization of a 4-halobenzaldehyde in thepresence of an alcohol, or diol. For example, the preparation ofcompound of formula (II a) with Hal being bromine, and R₁ and R₂ beingmethyl, is described in Journal of Organic Chemistry 1991, 56, 4280. Thecorresponding compound with R₁ and R₂ being ethyl can be prepared inethanol in the presence of triethyl orthoformate and an acid catalyst. Acompound of formula (III a) may be prepared, for example, byconventional acid catalyzed reaction of a 4-halobenzylalcohol with asuitable alkylating agent such as 3,4-dihydro-2H-pyran. For example, thepreparation of compound of formula (III a) wherein Hal is bromine, andR₃ is tetrahydropyran-2-yl, is described in Tetrahedron 1983, 39, 2531.

Several starting materials of formula (II c) with different protectinggroups Y are known in the art. The preparation of some examples isdescribed in EP 788487.

The following examples illustrate the invention described above;however, they are not intended to limit its extent in any manner, forexample, to specific reaction conditions.

EXAMPLE 1 Preparation of5-(4′-[1,3]dioxan-2-yl-biphenyl-2-yl)-2-(1-methyl-1-phenyl-ethyl)-2H-tetrazole

To magnesium turnings (0.882 g) are added under anhydrous conditions 12mL of a solution of 2-(4-bromo-phenyl)-[1,3]dioxane (8.02 g; 33 mmol) inanhydrous tetrahydrofuran (33 mL). The mixture is warmed to about 50°C., and five drops of 1,2-dibromoethane are added. After the reactionstarts, the mixture is heated to reflux and the remainder of thesolution of 2-(4-bromo-phenyl)-[1,3]dioxane is added over 40 minutes.The resulting mixture is further stirred at 60° C. for one hour andfinally allowed to cool down to room temperature. The concentration of4-([1,3]dioxan-2-yl)phenylmagnesium bromide in the solution above theexcess of magnesium turnings is 0.50 M according to titration.

In another flask, dichloro[1,3-bis(diphenylphosphino)propane]nickel(II)(0.022 g; 0.04 mmol) is suspended in tert-butyl methyl ether (3 mL) andcooled to about 0° C. before a 0.5 M solution of zinc chloride intetrahydrofuran (0.40 mL; 0.20 mmol) and a solution of5-(2-chloro-phenyl)-2-(1-methyl-1-phenyl-ethyl)-2H-tetrazole (1.20 g;4.0 mmol) in tert-butyl methyl ether (1.2 mL) are added. To thevigorously stirred resulting suspension is added at about 0° C. 9.6 mLof the above 0.5 M 4-([1,3]dioxan-2-yl)phenylmagnesium bromide solution(4.8 mmol) over one hour. The resulting dark brown solution is allowedto warm up and further stirred at room temperature for 20 hours. Themixture is cooled to about 0° C., quenched with 10 mL of a 3.8% solutionof ammonium chloride in water and diluted with ethyl acetate (25 mL).The aqueous phase is separated and extracted with ethyl acetate (25 mL).The combined organic phases are washed with a 0.5 M solution of sodiumhydroxide in water (10 mL) and with a 10% solution of sodium chloride inwater (10 mL). The combined organic phases are evaporated in vacuo. Asolution of the resulting pale green solid in a small amount of ethylacetate is filtered and evaporated. The resulting pale green solid ispurified by column chromatography on silica gel eluting with a 1:10mixture of tert-butyl methyl ether and toluene to afford5-(4′-[1,3]dioxan-2-yl-biphenyl-2-yl)-2-(1-methyl-1-phenylethyl)-2H-tetrazoleas colorless crystals.

¹H-NMR (400 MHz, d₆-DMSO): 1.47-1.52 (m, 1H), 2.01 (s, 6H), 2.02-2.07(m, 1H), 3.96-4.02 (m, 2H), 4.17-4.21 (m, 2H), 5.55 (s, 1H), 6.95-6.98(m, 2H), 7.10-7.13 (m, 2H), 7.32-7.39 (m, 5H), 7.51-7.53 (m, 1H),7.56-7.61 (m, 1H), 7.65-7.69 (m, 1H), 7.78-7.80 (m, 1H). Melting range:102-106° C.

EXAMPLE 2 Preparation of5-(4′-diethoxymethyl-biphenyl-2-yl)-2-(tetrahydro-pyran-2-yl)-2H-tetrazole

To magnesium turnings (2.92 g) is added under anhydrous conditions onefifth of a solution of 1-bromo-4-(diethoxymethyl)benzene (25.9 g; 100mmol) in anhydrous tetrahydrofuran (80 mL). The mixture is warmed toabout 40° C. and 1,2-dibromoethane (0.09 mL; 1.0 mmol) is added. Afterthe reaction starts, the remainder of the solution of1-bromo-4-(diethoxymethyl)benzene is added over one hour. The resultingmixture is further stirred at 40° C. for two hours and at roomtemperature for 30 minutes and is finally diluted by adding anhydroustetrahydrofuran (25 mL). The concentration of4-(diethoxymethyl)phenylmagnesium bromide in the solution above theexcess of magnesium turnings is 0.46 M according to titration.

In another flask, dichloro[1,3-bis(diphenylphosphino)propane]nickel(II)(0.027 g; 0.05 mmol) is suspended in tert-butyl methyl ether (3.8 mL)and cooled to about 0° C. before a 0.5 M solution of zinc chloride intetrahydrofuran (0.50 mL; 0.25 mmol) and a solution of a mixture of5-(2-chlorophenyl)-2-(tetrahydropyran-2-yl)-2H-tetrazole and5-(2-chlorophenyl)-1-(tetrahydropyran-2-yl)-1H-tetrazole (1.32 g; 5.0mmol) in tert-butyl methyl ether (1.3 mL) are added. To the vigorouslystirred resulting suspension is added at about 0° C. 13 mL of the above0.46 M 4-(diethoxymethyl)phenylmagnesium bromide solution (6.0 mmol)over one hour. The resulting black-yellow solution is stirred at about0° C. for 5 hours, allowed to warm up and further stirred at roomtemperature for 19 hours. The mixture is cooled to about 0° C. andquenched with a 7.5% solution of ammonium chloride in water (10 mL). Theaqueous phase is separated and extracted with ethyl acetate (25 mL). Thecombined organic phases are washed with water (10 mL), a 7.5% solutionof sodium carbonate in water (10 mL) and a 10% solution of sodiumchloride in water (10 mL). The combined organic phases are evaporated invacuo. A solution of the resulting brown-yellow oil in a small amount ofethyl acetate is filtered and evaporated. The resulting oil (2.68 g) ispurified by column chromatography on silica gel eluting with a 1:4mixture of ethyl acetate and hexane (in the presence of 0.2 volume-% oftriethylamine) to afford the main isomer (N2-isomer)5-(4′-diethoxymethyl-biphenyl-2-yl)-2-(tetrahydro-pyran-2-yl)-2H-tetrazoleas a colorless oil.

¹H-NMR of N2-isomer (400 MHz, CDCl₃): 1.24 (t, J=7.2 Hz, 6H), 1.60-1.67(m, 3H), 1.86-2.03 (m, 2H), 2.11-2.17 (m, 1H), 3.50-3.73 (m, 6H), 5.49(s, 1H), 5.97-5.99 (m, 1H), 7.17-7.20 (m, 2H), 7.37-7.39 (m, 2H),7.43-7.56 (m, 3H), 7.90-7.92 (m, 1H).

EXAMPLE 3 Preparation of5-(4′-[1,3]dioxan-2-yl-biphenyl-2-yl)-2-(tetrahydro-pyran-2-yl)-2H-tetrazoleand5-(4′-[1,3]dioxan-2-yl-biphenyl-2-yl)-1-(tetrahydro-pyran-2-yl)-1H-tetrazole

A suspension of magnesium turnings (2.68 g) in anhydrous tetrahydrofuran(20 mL) is cooled to 10° C. and five drops of 1,2-dibromoethane areadded. 2 mL of a solution of 2-(4-bromophenyl)-[1,3]dioxane (24.3 g; 100mmol) in anhydrous tetrahydrofuran (80 mL) is added at 10° C. undervigorous stirring. After the reaction starts the remainder of thesolution of 2-(4-bromo-phenyl)-[1,3]dioxane is added over 90 minutes.The resulting mixture is further stirred at about 16° C. for 2 hours andat 25° C. for 75 minutes. The concentration of4-([1,3]dioxan-2-yl)phenylmagnesium bromide in the solution above theexcess of magnesium turnings is about 0.90 M. In another flask,dichloro[1,3-bis(diphenylphosphino)propane]nickel(II) (0.054 g; 0.10mmol) is suspended in 1,2-dimethoxyethane (7.7 mL) and cooled to about0° C. before a 0.5 M solution of zinc chloride in tetrahydrofuran (1.0mL; 0.50 mmol) and a solution of a mixture of5-(2-chlorophenyl)-2-(tetrahydropyran-2-yl)-2H-tetrazole and5-(2-chlorophenyl)-1-(tetrahydropyran-2-yl)-1H-tetrazole (2.65 g; 10.0mmol) in 1,2-dimethoxyethane (2.7 mL) are added. To the vigorouslystirred resulting suspension is added at about 0° C. 13.4 mL of theabove 0.90 M 4-([1,3]dioxan-2-yl)phenylmagnesium bromide solution (12.0mmol) over one hour. The resulting brown-yellow solution is allowed towarm up and further stirred at room temperature for 3 hours. The mixtureis cooled to about 0° C. and quenched with a 7.5% solution of ammoniumchloride in water (20 mL). The aqueous phase is separated and extractedwith ethyl acetate (50 mL). The combined organic phases are washed withwater (20 mL), a 7.5% solution of sodium carbonate in water (20 mL) andwater (20 mL). The combined organic phases are evaporated in vacuo. Asolution of the resulting oil in a small amount of ethyl acetate isfiltered and evaporated. The resulting oil is purified by columnchromatography on silica gel eluting with a 1:2 mixture of ethyl acetateand hexane to afford the main isomer (N2-isomer)5-(4′-[1,3]dioxan-2-yl-biphenyl-2-yl)-2-(tetrahydro-pyran-2-yl)-2H-tetrazoleas a colorless oil and the minor isomer (N-1-isomer)5-(4′-[1,3]dioxan-2-yl-biphenyl-2-yl)-1-(tetrahydro-pyran-2-yl)-1H-tetrazoleas colorless crystals.

¹H-NMR of N2-isomer (400 MHz, CDCl₃): 1.42-1.47 (m, 1H), 1.57-1.65 (m,3H), 1.79-1.87 (m, 1H), 1.96-2.03 (m, 1H), 2.10-2.27 (m, 2H), 3.60-3.69(m, 2H), 3.95-4.01 (m, 2H), 4.23-4.27 (m, 2H), 5.48 (s, 1H), 5.98-6.00(m, 1H), 7.18-7.21 (m, 2H), 7.38-7.42 (m, 3H), 7.46-7.54 (m, 2H),7.89-7.91 (m, 1H).

¹H-NMR of N1-isomer (400 MHz, CDCl₃): 0.98-1.02 (m, 1H), 1.31-1.36 (m,1H), 1.42-1.47 (m, 2H), 1.51-1.61 (m, 1H), 1.87-1.96 (m, 2H), 2.14-2.26(m, 1H), 3.25-3.31 (m, 1H), 3.70-3.75 (m, 1H), 3.93-4.00 (m, 2H),4.22-4.27 (m, 2H), 4.84-4.87 (m, 1H), 5.45 (s, 1H), 7.12-7.15 (m, 2H),7.40-7.42 (m, 2H), 7.50-7.68 (m, 4H).

Melting range of N1-isomer: 125-127° C.

EXAMPLE 4 Preparation of 2′-(1H-tetrazol-5-yl)-biphenyl-4-carbaldehyde

A suspension of magnesium turnings (6.31 g) in anhydrous tetrahydrofuran(59 mL) is cooled to 14° C., treated with a 1 M solution ofdiisobutylaluminum hydride in tetrahydrofuran (2.35 mL, 2.4 mmol) andstirred for 20 min. At 14° C., 1-bromo-4-dimethoxymethyl-benzene (2.72g; 11.7 mmol) is added under vigorous stirring. After the reactionstarts, more 1-bromo-4-dimethoxymethyl-benzene (51.79 g; 223 mmol) isadded over 45 minutes, while the mixture is diluted with two portions ofanhydrous tetrahydrofuran (59 mL each). The resulting mixture is furtherstirred at about 25° C. for 2.5 hours. The concentration of4-(dimethoxymethyl)phenylmagnesium bromide in the solution above theexcess of magnesium turnings is about 1.0 M. In another flask, a mixtureof 5-(2-chlorophenyl)-2-(tetrahydropyran-2-yl)-2H-tetrazole and5-(2-chlorophenyl)-1-(tetrahydropyran-2-yl)-1H-tetrazole (98.2% content;53.91 g; 200 mmol) is dissolved in anhydrous tetrahydrofuran (37 mL)under an inert atmosphere anddichloro[1,2-bis(diphenylphosphino)ethane]nickel(II) (0.862 g; 1.60mmol) and a 0.5 M solution of zinc chloride in tetrahydrofuran (6.0 mL;3.0 mmol) are added. The vigorously stirred resulting suspension iscooled to about 14° C. and the above 1.0 M4-(dimethoxymethyl)phenylmagnesium bromide solution (229 mL; 230 mmol)is added over one hour while keeping the temperature below 25° C. byexternal cooling. The dark brown reaction mixture is stirred at roomtemperature for 17.5 hours. After that, more than 99% of the startingmaterial is converted, and methanol (8.0 mL) is added to the mixture.

A part of the solvents (about 156 mL) are distilled off under reducedpressure. Ethanol (307 mL in total) is added while more solvents aredistilled off. To the resulting brown mixture is added at 50° C. over 10minutes a mixture of a 2 M aqueous sulfuric acid solution (32 mL; 64mmol) and water (75 mL). The mixture is further stirred at 50° C. for 50minutes, at 60° C. for 1.5 hours and at 35° C. overnight. The mixture isstirred at 60° C. with activated carbon (5.3 g) and filter aid (2.7 g)for 40 minutes in total and is then filtered at about 55° C. The orangefiltrate is concentrated by distilling off about 202 mL of solventsunder reduced pressure. After adding water (48 mL) at 50° C., thestirred resulting suspension is allowed to cool to room temperatureovernight and is further stirred at about 10° C. for 90 minutes. Thesolids are collected by filtration, washed with a 1:2 mixture of ethanoland water and water and are dried under reduced pressure at about 60° C.to afford 2′-(1H-tetrazol-5-yl)-biphenyl-4-carbaldehyde as pale yellow,crystalline solid.

Melting range: 188.6-189.9° C.

EXAMPLE 5 Preparation of5-(4′-diethoxymethyl-biphenyl-2-yl)-2-(tetrahydro-pyran-2-yl)-2H-tetrazole

To a suspension of magnesium turnings (5.11 g) in anhydroustetrahydrofuran (40 mL) is added 1,2-dibromoethane (0.106 mL; 1.2 mmol).The suspension is cooled to 12° C. and 6 mL of a solution of1-bromo-4-(diethoxymethyl)benzene (53.6 g; 200 mmol) in anhydroustetrahydrofuran (120 mL) and a second portion of 1,2-dibromoethane(0.106 mL; 1.2 mmol) are added. After the reaction starts the remainderof the solution of 1-bromo-4-(diethoxymethyl)benzene is added over 90minutes. The resulting mixture is further stirred at 20 to 25° C. for2.5 hours. The mixture is diluted with anhydrous tetrahydrofuran to atotal volume of 250 mL. The concentration of4-(diethoxymethyl)phenylmagnesium bromide in the solution above theexcess of magnesium turnings is about 0.78 M. In another flask are addedto dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloromethane adduct (0.012 g; 0.015 mmol) a 0.5 M zinc chloridesolution in tetrahydrofuran (0.6 mL; 0.30 mmol) and a solution of amixture of 5-(2-bromophenyl)-2-(tetrahydropyran-2-yl)-2H-tetrazole and5-(2-bromophenyl)-1-(tetrahydropyran-2-yl)-1H-tetrazole (4.99 g; 14.3mmol) in tetrahydrofuran (30 mL). To the stirred resulting yellow-orangesolution is added at room temperature 22.2 mL of the above 0.78 M4-(diethoxymethyl)phenylmagnesium bromide solution (17.3 mmol) over twohours. The resulting orange solution is further stirred at roomtemperature for 18 hours. After that, no more starting material could bedetected by thin layer chromatography. The mixture is cooled to about 0°C. and a solution of sodium hydrogencarbonate (2.0 g) in water (25 mL)and ethyl acetate (30 mL) are added. The aqueous phase is separated andextracted with ethyl acetate (40 mL). The combined organic phases arewashed with a solution of sodium hydrogencarbonate (2.0 g) in water (25mL) and twice with water (25 mL) before they are evaporated in vacuo.The resulting orange oil is purified by column chromatography on silicagel eluting with a 1:4 mixture of ethyl acetate and hexane (in thepresence of 0.3 volume-% of triethylamine) to afford the main isomer(N2-isomer)5-(4′-diethoxymethyl-biphenyl-2-yl)-2-(tetrahydro-pyran-2-yl)-2H-tetrazoleas a pale yellow oil.

¹H-NMR of N2-isomer (400 MHz, CDCl₃): 1.24 (t, J=7.2 Hz, 6H), 1.59-1.67(m, 3H), 1.85-2.03 (m, 2H), 2.11-2.18 (m, 1H), 3.50-3.74 (m, 6H), 5.49(s, 1H), 5.97-5.99 (m, 1H), 7.17-7.20 (m, 2H), 7.38-7.40 (m, 2H),7.43-7.56 (m, 3H), 7.90-7.92 (m, 1H).

EXAMPLE 6 Preparation of 2′-(1H-tetrazol-5-yl)-biphenyl-4-carbaldehyde

To5-(4′-diethoxymethyl-biphenyl-2-yl)-2-(tetrahydropyran-2-yl)-2H-tetrazole(0.408 g; 1.00 mmol) are added 94% ethanol (2.5 mL) and a 2N aqueoussolution of hydrochloric acid (0.5 mL; 1.0 mmol). The resulting solutionis heated to 45° C. for 3 hours. After the addition of water (about 2mL) the mixture is allowed to cool down to room temperature and thenstirred at 0 to 5° C. for 30 minutes. The resulting suspension isfiltered and the solids are washed with a small amount of water, driedin vacuo at 40° C. to afford2′-(1H-tetrazol-5-yl)-biphenyl-4-carbaldehyde as white, crystallinepowder.

Melting point: 187.5-190.0° C.

EXAMPLE 7 Preparation of5-(4′-dimethoxymethyl-biphenyl-2-yl)-2-(tetrahydro-pyran-2-yl)-2H-tetrazolein the presence of a nickel catalyst and in the absence of a zinc salt

A suspension of magnesium turnings (2.35 g) in anhydrous tetrahydrofuran(66 mL) is cooled to 14° C., treated with a 1 M solution ofdiisobutylaluminum hydride in tetrahydrofuran (1.8 mL; 1.8 mmol) andstirred for 20 min. At 14° C., 1-bromo-4-dimethoxymethyl-benzene (1.02g; 4.4 mmol) is added under vigorous stirring. After the reactionstarts, more 1-bromo-4-dimethoxymethyl-benzene (19.32 g; 83.6 mmol) isadded over 50 minutes. The resulting mixture is further stirred at about25° C. for 2.5 hours. The concentration of4-(dimethoxymethyl)phenylmagnesium bromide in the solution above theexcess of magnesium turnings is about 0.96 M. In another flask, amixture of 5-(2-chlorophenyl)-2-(tetrahydropyran-2-yl)-2H-tetrazole and5-(2-chlorophenyl)-1-(tetrahydropyran-2-yl)-1H-tetrazole (94% content;4.22 g; 15.0 mmol) is dissolved in anhydrous tetrahydrofuran (2.8 mL)under an inert atmosphere anddichloro[1,2-bis(diphenylphosphino)ethane]nickel(II) (80.8 mg; 0.15mmol) is added. The vigorously stirred resulting suspension is cooled toabout 15° C. and the above 0.96 M 4-(dimethoxymethyl)phenylmagnesiumbromide solution (18 mL; 17.3 mmol) is added over one hour while keepingthe temperature below 25° C. by external cooling. The dark brownreaction mixture is agitated at room temperature for 22.5 hours. Afterthat, about 94% of the starting material are converted. Methanol (1.2mL; 30 mmol) is added to the mixture followed by isopropyl acetate (35mL), a solution of ammonium chloride (0.4 g) in water (10 mL) and water(10 mL). The layers are separated. The organic layer is washed withwater (10 mL), three times with a solution of sodium hydrogencarbonate(1.0 g) in water (12 mL) and twice with water (10 mL) before it isevaporated in vacuo. The resulting brown oil is purified by columnchromatography on silica gel eluting with a 1:4 mixture of ethyl acetateand hexane (in the presence of 0.3 volume-% of triethylamine) to affordthe main isomer (N2-isomer)5-(4′-dimethoxymethyl-biphenyl-2-yl)-2-(tetrahydro-pyran-2-yl)-2H-tetrazoleas a pale yellow oil. ¹H-NMR of N2-isomer (400 MHz, CDCl₃): 1.59-1.68(m, 3H), 1.86-1.93 (m, 1H), 1.96-2.04 (m, 1H), 2.12-2.20 (m, 1H), 3.34(s, 6H), 3.65-3.76 (m, 2H), 5.38 (s, 1H), 5.95-5.98 (m, 1H), 7.18-7.21(m, 2H), 7.36-7.38 (m, 2H), 7.44-7.56 (m, 3H), 7.90-7.92 (m, 1H).

EXAMPLE 8 Attempt for the preparation of5-(4′-dimethoxymethyl-biphenyl-2-yl)-2-(tetrahydro-pyran-2-yl)-2H-tetrazolein the absence of a catalyst

A mixture of 5-(2-chlorophenyl)-2-(tetrahydropyran-2-yl)-2H-tetrazoleand 5-(2-chlorophenyl)-1-(tetrahydropyran-2-yl)-1H-tetrazole (94%content; 4.22 g; 15.0 mmol; same batch as used in Example 7) isdissolved in anhydrous tetrahydrofuran (2.8 mL) under an inertatmosphere. The vigorously stirred resulting suspension is cooled toabout 15° C. and a 0.96 M 4-(dimethoxymethyl)phenylmagnesium bromidesolution (18 mL; 17.3 mmol; same batch as used in Example 7) is addedover one hour while keeping the temperature below 25° C. by externalcooling. The brown reaction mixture is agitated at room temperature for22 hours. After that, HPLC analysis is done on a sample which is, asusual, hydrolyzed with dilute aqueous hydrochloric acid. The analysisshows mainly unconverted starting material (detected as5-(2-chlorophenyl)-1H-tetrazole) and less than 0.25 area % ofC—C-coupling product (detected as2′-(1H-tetrazol-5-yl)-biphenyl-4-carbaldehyde). Finally, when methanol(1.2 mL; 30 mmol) is added to the mixture, an unusually strong exothermis observed which indicates that most of the4-(dimethoxymethyl)phenylmagnesium bromide is still present after atotal reaction time of 23 hours.

EXAMPLE 9 Preparation of2-(tetrahydro-pyran-2-yl)-5-[4′-(tetrahydro-pyran-2-yloxymethyl)-biphenyl-2-yl]-2H-tetrazole

A suspension of magnesium turnings (0.48 g) in anhydrous tetrahydrofuran(13.5 mL) is cooled to 14° C., treated with a 25 weight % solution ofdiisobutylaluminium hydride in toluene (0.24 mL; 0.36 mmol) and stirredfor 20 min. At 14° C., 2-(4-bromo-benzyloxy)-tetrahydro-pyran (94.5%content; 0.26 g; 0.90 mmol) is added under vigorous stirring. After thereaction starts, more 2-(4-bromo-benzyloxy)-tetrahydro-pyran (94.5%content; 4.91 g; 17.1 mmol) is added over 40 minutes. The resultingmixture is further stirred at about 25° C. for 2.5 hours. Thetheoretical concentration of4-(tetrahydro-pyran-2-yloxymethyl)phenylmagnesium bromide in thesolution above the excess of magnesium turnings is about 0.95 M. Inanother flask, a mixture of5-(2-chlorophenyl)-2-(tetrahydropyran-2-yl)-2H-tetrazole and5-(2-chlorophenyl)-1-(tetrahydropyran-2-yl)-1H-tetrazole (94% content;4.22 g; 15.0 mmol) is dissolved in anhydrous tetrahydrofuran (2.8 mL)under an inert atmosphere anddichloro[1,2-bis(diphenylphosphino)ethane]nickel(II) (80.8 mg; 0.15mmol) and a 0.5 M zinc chloride solution in tetrahydrofuran (0.45 mL;0.23 mmol) are added. The vigorously stirred resulting suspension iscooled to about 15° C. and the above4-(tetrahydro-pyran-2-yloxymethyl)phenylmagnesium bromide solution (19mL; 18 mmol) is added over one hour while keeping the temperature below25° C. by external cooling. The brown reaction mixture is stirred atroom temperature for 17.5 hours. After that, about 97% of the startingmaterial are converted according to HPLC analysis. Methanol (1.2 mL; 30mmol) is added to the mixture followed by isopropyl acetate (40 mL), asolution of ammonium chloride (0.4 g) in water (10 mL) and water (10mL). The layers are separated. The organic layer is washed with water(10 mL) and three times with a solution of sodium hydrogencarbonate (1.0g) in water (12 mL). The aqueous layer is extracted with isopropylacetate (50 mL). The combined organic layers are washed twice with water(10 mL) and are evaporated in vacuo. The resulting greenish oil ispurified by column chromatography on silica gel eluting with a 1:4mixture of ethyl acetate and hexane (in the presence of 0.3 volume-% oftriethylamine) to afford the main isomer (N2-isomer)2-(tetrahydro-pyran-2-yl)-5-[4′-(tetrahydro-pyran-2-yloxymethyl)-biphenyl-2-yl]-2H-tetrazoleas a colorless oil.

Mass spectrum (ESI+): m/z=421 [M+H]⁺ and m/z=438 [M+NH₄]⁺.

EXAMPLE 10 Preparation of [2′-(1H-tetrazol-5-O-biphenyl-4-yl]-methanol

To2-(tetrahydro-pyran-2-yl)-5-[4′-(tetrahydro-pyran-2-yloxymethyl)-biphenyl-2-yl]-2H-tetrazole(3.36 g; 8.00 mmol) are added 94% ethanol (12 mL) and a 2 M aqueoussolution of sulfuric acid (1.0 mL; 2.0 mmol). The resulting mixture isheated to 45° C. for 3.5 hours. Water (16 mL) is slowly added and themixture is allowed to cool down to room temperature. The pH of thereaction mixture is adjusted to pH 2 to 3 by adding a 2M aqueous sodiumhydroxide solution (0.6 mL). The mixture is concentrated under reducedpressure, diluted with isopropyl acetate (15 mL) and washed three timeswith water (3 mL). The organic extract is concentrated under reducedpressure to a volume of about 4 mL and tert-butyl methyl ether (8 mL intotal) is slowly added. The mixture is stirred overnight, diluted with asmall amount of isopropyl acetate and further stirred for 4.5 hours. Thesuspended, white solid is filtered, washed with a small amount ofisopropyl acetate and dried under reduced pressure to afford[2′-(1H-tetrazol-5-yl)-biphenyl-4-yl]-methanol. The filtrate isconcentrated under reduced pressure, and tert-butyl methyl ether (3 mL)and heptane (0.5 mL) are slowly added. The mixture is stirred at roomtemperature overnight and at 0 to 5° C. for 1 hour. The suspended, whitesolid is filtered, washed with a small amount of isopropyl acetate anddried under reduced pressure to afford a second crop of[2′-(1H-tetrazol-5-yl)-biphenyl-4-yl]-methanol.

Melting range: 132.4-134.6° C.

EXAMPLE 11 Preparation of 2′-(1H-tetrazol-5-yl)-biphenyl-4-carbaldehyde

A mixture of [2′-(1H-tetrazol-5-yl)-biphenyl-4-yl]-methanol (1.03 g; 4.0mmol), triethylamine (2.80 mL; 20 mmol) and dimethylsulfoxide (2 mL) iscooled to 12° C., and a solution of sulfur trioxide pyridine complex(1.27 g; 8.0 mmol) in dimethylsulfoxide (6.4 mL) is added over 10minutes. The resulting clear solution is stirred at room temperature foralmost 48 hours during which time more triethylamine (0.28 mL; 2.0 mmol)is added. The mixture is diluted with ethyl acetate (10 mL), cooled to 0to 5° C. and slowly treated with a 2 M aqueous hydrochloric acidsolution (15 mL). The aqueous layer is separated and extracted withethyl acetate (10 mL). The combined organic layers are diluted withethyl acetate (10 mL), washed with a 2 M aqueous hydrochloric acidsolution (15 mL), twice with a 1 M aqueous hydrochloric acid solution(10 mL) and with a 10% aqueous solution of sodium chloride (10 mL). Theorganic extract is concentrated at 45° C. under reduced pressure to avolume of about 4 to 5 mL. The resulting suspension is stirred at roomtemperature for 45 minutes and at 0 to 5° C. for one hour before it isfiltered. The solids are washed with cold ethyl acetate (2 mL) and driedat 45° C. under reduced pressure to give2′-(1H-tetrazol-5-yl)-biphenyl-4-carbaldehyde as white, crystallinesolid. A second crop can be obtained by concentrating the mother liquorto a volume of about 1 mL and filtering the solid formed.

Melting range: 188.2-189.3° C.

1. A process for the manufacture of the compound of formula (I)

wherein Y represents a tetrazole protecting group, and R₁ and R₂,independently of one another, represent C₁-C₁₀-alkyl, or R₁ and R₂combined together form C₂-C₁₀-alkylene; comprising (a) reacting acompound of formula (II a)

wherein Hal is chlorine, bromine or iodine, with an active form ofmagnesium in an appropriate solvent (b) reacting a resulting arylmagnesium halide compound of formula (II b)

in the presence of a transition metal catalyst with a compound offormula (II c)

wherein X is chlorine, in the absence of a metal salt additive; and, ifnecessary, isolating a resulting compound of formula (I).
 2. A processaccording to claim 1, wherein a transition metal catalyst is a complexof nickel(0), or a complex of nickel(II) salt with at least oneorganophosphorus compound containing trivalent phosphorus; or atransition metal catalyst is a nickel(II) complex with anorganophosphorus ligand which contains two trivalent phosphorus atoms.3. A process for the manufacture of the compound of formula (I C)

wherein Y represents a tetrazole protecting group, and R₃ represents ahydroxyl protecting group; comprising reacting an aryl magnesium halidecompound of formula (III b)

wherein Hal is chlorine, bromine or iodine, in the presence of atransition metal catalyst and a catalytically effective amount of ametal salt additive, with a compound of formula (II c)

wherein X is a substituent which, when bound to a phenyl ring, is notconsiderably replaceable at room temperature by an aryl magnesium halidereagent of formula (III b) in the absence of a catalyst; and, ifnecessary, isolating a resulting compound of formula (I C).
 4. A processaccording to claim 3, wherein an aryl magnesium halide reagent offormula (III b) is prepared by reacting a compound of formula (III al

wherein R₃ and Hal have meanings as defined in claim 3, with an activeform of magnesium in an appropriate solvent.
 5. A process according toclaim 3, which process further comprises deprotecting a compound offormula (I C) to afford a compound of formula (I B)


6. A process according to claim 5, which process further comprisestreating a compound of formula (I B) with an oxidizing agent in thepresence of a suitable solvent to afford a compound of formula (I A)


7. A process according to claim 3, wherein variable Y is selected fromthe group consisting of 1-butoxyethyl, 1-ethoxyethyl,2-tetrahydropyranyl and 2-tetrahydrofuranyl.
 8. A process according toclaim 3, wherein a transition metal catalyst is a complex of atransition metal or a transition metal salt and one, two or up to fourcoordinating ligands selected from the group consisting oftriphenylphosphine, tri(ortho-tolyl)phosphine, tri(para-tolyl)phosphine,trimethylphosphine, triethylphosphine, tributylphosphine,tri(1,1-dimethylethyl)phosphine, tricyclopentylphosphine,tricyclohexylphosphine, trimethylphosphite, triethylphosphite,tri(1-methylethyl)phosphite, tricyclopentylphosphite,tricyclohexylphosphite, 1,2-bis(diphenylphosphino)ethane,1,3-bis(diphenylphosphino)propane, 1,4-bis(diphenylphosphino)butane,1,1′-bis(diphenylphosphino)ferrocene,1,1′-bis(di-[2-propyl]-phosphino)ferrocene,1,1′-bis(di-tert-butylphosphino)ferrocene,1,2-bis(diphenylphosphino)benzene,2,2′-bis(diphenylphosphino)-1,1′-biphenyl,2,2′-bis(diphenylphosphino)-1,1′-binaphtyl,bis(2-diphenylphosphinophenyl)ether and9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene.
 9. A process accordingto claim 8, wherein a transition metal salt is selected from the groupconsisting of nickel(II) chloride, nickel(II) bromide and nickel(II)acetylacetonate.
 10. A process according to claim 8, wherein atransition metal catalyst is selected from the group consisting ofdichlorobis(triphenylphosphine)nickel(II),dichloro[1,2-bis(diphenylphosphino)ethane]nickel(II) anddichloro[1,3-bis(diphenylphosphino)propane]-nickel(II).
 11. A processaccording to claim 8, wherein a transition metal salt is selected fromthe group consisting of palladium(II) chloride, palladium(II) bromideand palladium(II) acetate.
 12. A process according to claim 8, wherein atransition metal catalyst is selected from the group consisting ofdichlorobis(triphenylphosphine)palladium(II),dichloro[1,3-bis(diphenylphosphino)propane]palladium(II) anddichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II), or adichloromethane adduct thereof.
 13. A process according to claim 3wherein a metal salt additive is selected from the group consisting of acopper(I), copper(II), zinc(II), silver(I), cadmium(II), mercury(II),aluminum(III), gallium(III), indium(III), tin(IV), titanium(IV) andzirconium(IV) salt.
 14. A process according to claim 13, wherein theamount of metal salt additive used is between 0.1 and 8 molar % relativeto a compound of formula (II c).
 15. A process according to claim 3,wherein X is chlorine; and a transition metal catalyst is a complex ofnickel(0), or a complex of nickel(II) salt with at least oneorganophosphorus compound containing trivalent phosphorus; or atransition metal catalyst is a nickel(II) complex with anorganophosphorus ligand which contains two trivalent phosphorus atoms.16. A process according to claim 15, wherein a transition metal catalystis dichloro[1,2-bis(diphenylphosphino)ethane]nickel(II); and a metalsalt additive is ZnCl₂ or ZnBr₂.
 17. A process according to claim 3,wherein X is bromine; and a transition metal catalyst is a complex ofpalladium(0), or a complex of a palladium(II) salt with at least oneorganophosphorus compound containing trivalent phosphorus; or atransition metal catalyst is a palladium(II) complex with anorganophosphorus ligand which contains two trivalent phosphorus atoms.18. A process according to claim 17, wherein a transition metal catalystis dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II), or adichloromethane adduct thereof; and a metal salt additive is ZnCl₂ orZnBr₂.
 19. A process according to claim 3, wherein a transition metalcatalyst is an uncomplexed transition metal which is selected from thegroup consisting of nickel, palladium, platinum, cobalt, manganese orcopper; or wherein a transition metal catalyst is an uncomplexedtransition metal salt which is selected from the group consisting ofnickel(II), palladium(II), platinum(II), cobalt(II), manganese(II),copper(I) or copper (II) chloride, bromide, iodide, hydroxide, oxide,acetate, hydroxyacetate, propionate, succinate, trifluoroacetate,acetylacetonate, nitrate, cyanide, sulfate, trifluoromethanesulfonate,methanesulfonate, benzenesulfonate or p-toluenesulfonate thereof.
 20. Aprocess for the manufacture of the compound of formula (I)

wherein Y represents a tetrazole protecting group, and R₃ represents ahydroxyl protecting group; comprising (a′) reacting a compound offormula (III a)

wherein Hal is chlorine, bromine or iodine, with an active form ofmagnesium in an appropriate solvent; (b′) reacting a resulting arylmagnesium halide compound of formula (III b)

in the presence of a transition metal catalyst with a compound offormula (II c)

wherein X is chlorine, in the absence of a metal salt additive; and, ifnecessary, isolating a resulting compound of formula (I C).
 21. Aprocess according to claim 20, wherein a transition metal catalyst is acomplex of nickel(0), or a complex of nickel(II) salt with at least oneorganophosphorus compound containing trivalent phosphorus; or atransition metal catalyst is a nickel(II) complex with anorganophosphorus ligand which contains two trivalent phosphorus atoms.22. A compound of formula (I C)

wherein Y represents a tetrazole protecting group, and R₃ represents ahydroxyl protecting group.
 23. A compound according to claim 22, whereinY and R₃, independently of one another, are 1-butoxyethyl,1-ethoxyethyl, 2-tetrahydropyranyl or 2-tetrahydrofuranyl.